Periodic Reporting for period 1 - PreCODE (Identifying the role of injury-associated cellular reprogramming in the early oncogenic transformation of human colonic epithelium)
Période du rapport: 2023-09-01 au 2025-08-31
Colorectal cancer (CRC) is the second leading cause of cancer-related deaths globally, making it a critical public health and healthcare challenge. Patients with ulcerative colitis (UC), a chronic inflammatory disease of the colon, are at particularly high risk of developing colitis-associated CRC. Despite this well-established link, the precise mechanisms by which epithelial injury and inflammation contribute to tumor initiation remain unclear, limiting opportunities for effective prevention and early intervention. This project addresses this gap by investigating how injury alters the vulnerability of colonic epithelial cells to oncogenic transformation, using advanced human organoid and CRISPR-based models. By uncovering how early mutations interact with injury states to shift epithelial recovery trajectories, the project aims to identify novel windows for early CRC detection and intervention. In the broader political and strategic context of rising cancer incidence and the urgent need for preventive oncology, these insights could inform new approaches to monitoring high-risk patient populations and ultimately reduce the global burden of CRC.
In this project, I investigated how injury influences early colonic transformation. First, leveraging my expertise in cancer modeling with 3D human-derived organoids and CRISPR technology, I established a model system to study this process. First, I demonstrated that human colonic organoids undergo injury-like cell state changes during passaging, mirroring observations from previously published murine models. This provided a reliable platform to examine how CRC-associated mutations affect the epithelium when introduced during an injury-like state.
To this end, I generated inducible overexpression models for key CRC oncogenes, including KRAS, BRAF, and PIK3CA, and analyzed their impact on epithelial gene expression when activated during the injury-like state. The most comprehensive follow-up focused on the KRAS model. Our findings showed that even a single oncogenic event such as KRAS overexpression disrupted the normal injury–recovery trajectory. Rather than returning to homeostasis, the epithelium shifted into an alternative gene expression state that persisted over time. This indicates that cells are particularly vulnerable to oncogenic mutations during injury and may acquire stable, tumor-promoting traits.
Future work will address whether this altered trajectory is reversible and how such vulnerabilities might be exploited for earlier detection or novel therapeutic strategies in CRC.
To this end, I generated inducible overexpression models for key CRC oncogenes, including KRAS, BRAF, and PIK3CA, and analyzed their impact on epithelial gene expression when activated during the injury-like state. The most comprehensive follow-up focused on the KRAS model. Our findings showed that even a single oncogenic event such as KRAS overexpression disrupted the normal injury–recovery trajectory. Rather than returning to homeostasis, the epithelium shifted into an alternative gene expression state that persisted over time. This indicates that cells are particularly vulnerable to oncogenic mutations during injury and may acquire stable, tumor-promoting traits.
Future work will address whether this altered trajectory is reversible and how such vulnerabilities might be exploited for earlier detection or novel therapeutic strategies in CRC.
The project successfully developed a human organoid–based model to study CRC initiation in the context of epithelial injury. It provided proof that injury-like states sensitize epithelial cells to oncogenic transformation, with KRAS overexpression leading to stable and potentially irreversible deviations from normal recovery. These results lay the groundwork for future research into both mechanistic understanding and translational opportunities in CRC prevention, early detection, and treatment.
To ensure further uptake and translation of these results, several needs have been identified:
• Further research and validation: Expanded studies are required to test reversibility of the altered epithelial states, to extend analysis beyond KRAS to other oncogenes, and to validate findings in patient-derived tissues.
• Technological demonstration: Proof-of-concept work demonstrating how biomarkers of injury-linked oncogenic transformation could be detected in clinical samples is a key next step.
• Access to markets and partnerships: Collaborations with diagnostic companies and clinical research consortia will be essential to bring these insights toward early CRC detection strategies.
• Commercialisation and IPR support: Protection of intellectual property related to biomarkers or intervention strategies could support the translation of findings into diagnostic or therapeutic products.
• Supportive regulatory and standardisation frameworks: Engagement with regulators will be necessary to align biomarker validation pipelines with clinical requirements.
• Internationalisation: Given the global burden of CRC, international partnerships will be important both for validating findings across diverse patient populations and for scaling potential interventions.
To advance this research, we have secured additional funding from the Danish Cancer Society to further build on our findings.
To ensure further uptake and translation of these results, several needs have been identified:
• Further research and validation: Expanded studies are required to test reversibility of the altered epithelial states, to extend analysis beyond KRAS to other oncogenes, and to validate findings in patient-derived tissues.
• Technological demonstration: Proof-of-concept work demonstrating how biomarkers of injury-linked oncogenic transformation could be detected in clinical samples is a key next step.
• Access to markets and partnerships: Collaborations with diagnostic companies and clinical research consortia will be essential to bring these insights toward early CRC detection strategies.
• Commercialisation and IPR support: Protection of intellectual property related to biomarkers or intervention strategies could support the translation of findings into diagnostic or therapeutic products.
• Supportive regulatory and standardisation frameworks: Engagement with regulators will be necessary to align biomarker validation pipelines with clinical requirements.
• Internationalisation: Given the global burden of CRC, international partnerships will be important both for validating findings across diverse patient populations and for scaling potential interventions.
To advance this research, we have secured additional funding from the Danish Cancer Society to further build on our findings.